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The definition of anaphylaxis is 'a serious, life-threatening generalized or systemic hypersensitivity reaction' and is considered as the life threatening adverse drug reaction. We experienced a case of cefotetan induced anaphylaxis with negative pre-skin test, used for surgical prophylaxis. A 82-year-old female was scheduled for total knee replacement therapy. She had no previous history of allergy and her skin test results were also negative. On her right knee surgery, she underwent cefotetan therapy as a surgical prophylaxis for a week with no problems identified. Next left knee surgery, she also received the prophylaxis of intravenous cefotetan. However, a few minutes later, anaphylactic reaction developed with vomiting, severe hypotension, bronchospasm, and dyspnea. After immediate intensive care treatment, she recovered without significant complications. Though commonly used laboratory data in case reports, such as the specific IgE, tryptase, histamine, or allergic skin prick test were limited, we successfully confirmed anaphylaxis based on clinical criteria for diagnosing anaphylaxis based on WAO 2011 guideline with through concurrent patient°Øs medical history review and the process of identifying the causes.